The present invention relates to substituted phenylpropanoic acid derivatives, effective for the therapy of abnormality of lipidmetabolism as agonists of human peroxisome proliferant-activated receptor (abbreviated as PPAR), in particular, as agonists for human PPARxcex1 isoform, their addition salts and their hydrates, processes for preparing them, and medicinal compositions containing these compounds.
The peroxisome proliferant-activated receptor (PPAR)""s are a ligand-dependent transcription factors that belong to nuclear receptor superfamily, such as steroid receptor, retinoid receptor, thyroid receptor, etc. Three isoforms (xcex1 type, xcex2 (or xcex4) type and xcex3 type) with different histological distribution have been identified hitherto in human and various animal species (Proc. Natl. Acad. Sci., 1992, 89, 4653). Thereamong, the PPARxcex1 is distributed in the liver, kidney, etc., with high catabolic capacity for fatty acids and, in particular high expression is recognized in the liver, (Endo-crinology, 1995, 137, 354), positively or negatively controlling the expressions of genes relevant to the metabolism and the intracellular transport of fatty acids (e.g. acyl CoA synthetic enzyme, fatty acid-binding protein and lipoprotein lipase) and apolipoprotein (AI, AII, CIII) genes relevant to the metabolisms of cholesterol and neutral lipid. The PPARxcex2 is expressed ubiquitously in the tissues or organisms, including nerve cells. At present, the physiological significance of PPARxcex2 is unclear. The PPARxcex3 is highly expressed in the adipocytes and involved the differentiation of adipocytes (J. Lipid Res., 1996, 37, 907). In this way, each isoform of PPAR play specific function in the particular organs and tissues.
Moreover, it is reported that a knock-out mouse of PPARxcex1 exhibits hypertriglyceridemia with ageing and becomes obesity mainly by increasing the white adipose tissues (J. Biol. Chem., 1998, 273, 29577), hence the relevance between activation of PPARxcex1 and decreasing action of lipids (cholesterol and triglyceride) in blood is suggested strongly.
On the other hand, fibrates and statins are widely used so far as the therapeutic drugs for hyperlipidemia. However, the fibrates have only weak decreasing effect of cholesterol, while the statins have weak decreasing effect of free fatty acids and triglycerides. Moreover, with respect to the fibrates, various adverse effects such as gastrointestinal injury, anthema, headache, hepatic disorder, renal disorder and biliary calculus are reported. The reason is considered to be due to that the fibrates exhibit extensive pharmacological function, hence the development of a therapeutic drug for hyperlipidemia with specific mechanism is desired.
When considering the present situation of such conventional therapeutic drugs for hyperlipidemia, and the role on the adjusting mechanism of lipidmetabolism and the connection to the pathology of hyperlipidemia of transcription factor called PPARxcex1, which has become clear until now, if a compound that binds directly to as a ligand of PPARxcex1, in particular, human PPARxcex1 and is capable of activating human PPARxcex1 could be created, the medicinal use thereof would be expected as a compound that exhibits the decreasing effect of lipids (both of cholesterol and triglyceride) in blood due to very specific mechanism.
Prior arts
For compounds having an affinity to PPARxcex1 as ligands of PPARxcex1, eicosanoids in HETE (hydroxyeicosatetraenoic acid) group produced via oxidation with cytochrome P-450, in particular, 8-HETE, 8-HEPE, etc. are reported in addition to LTB4 being a metabolite of arachidonic acid (Proc. Natl. Acad. Sci., 1997, 94, 312). However, these endogenous unsaturated fatty acid derivatives are unstable metabolically and chemically and cannot be offered as medicinal drugs.
On the other hand, as compounds with similar structure to the inventive substituted phenylpropanoic acid derivatives, a group of compounds shown below, etc. are reported.
As compounds with glucose-lowering action, in International Publication Number WO98/28254 (Nippon Chemiphar Co., Ltd.), compounds represented by a general formula (A) 
(wherein A1 denotes aryl group which may have substituent or hetero-cycle group, Y2 denotes alkylene chain with carbon atoms of 1 to 5, X4 denotes bond hand, oxygen atom or sulfur atom, W1 denotes naphthalene ring which may have substituent, quinoline ring, indole ring, benzisoxazole ring or benzo[b]thiophene ring, R4 denotes hydrogen atom or alkyl group with carbon atoms of 1 to 8, X5 denotes oxygen atom or sulfur atom, and R5 denotes alkyl group with carbon atoms of 1 to 8 which may have substituent, aralkyl group or aryl group), are reported. These compounds however have different structure from that of the inventive compounds in that carbonyl group or amide group is not contained in Y2 and X4 being connecting portions and that W1 to bind to 3-position of propanoic acid is heterocycle, and it is also not described that these compounds have the binding activity to human PPARxcex1 and the transcription-activating function.
As propanoic acid derivatives with glucose-lowering action and lipid-decreasing effect, in International Publication Number WO98/07699 (Japan Tobacco Inc.), compounds represented by a general formula (B) 
(wherein R denotes a substituent represented by D1 or D2, R1 denotes aromatic ring, cycloalkyl group or heteroaromatic ring, R5 denotes alkyl group, R4 denotes hydrogen atom or alkyl group, R6 denotes hydrogen atom or it may be connected to R9 to form double bond, R7 denotes carboxyl group, acyl group, alkoxycarbonyl group which may have substituent, alkyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group, NHR8 group or OR8 group, R8 denotes acyl group which may have substituent or alkoxycarbonyl group, R9 denotes hydrogen atom, alkyl group or alkoxycarbonyl group, and R10 denotes hydrogen atom, amino group, alkoxy group, alkyl group, aryloxy group or aralkyloxy group), are reported. However, these compounds also have different structure from that of the inventive compounds in that substituents on benzene ring are of disubstituted form at 1-position and 4-position, and it is also not described that these compounds have the binding activity to human PPARxcex1 and the transcription-activating function.
As carboxylic acid derivatives with agonistic effect on leukotriene receptor, in Jpn. Kokai Tokkyo Koho JP 63-91354 (Yamanouchi Pharmaceutical Co., Ltd.), compounds represented by a general formula (C) 
(wherein A denotes hydrogen atom or phenyl group, m denotes integer of 3 to 10, n denotes integer of 1 to 6, X denotes CONH group or NHCO group, and R denotes carboxy lower alkyl group or carboxy lower alkylcarbamoyl group (however, when A is phenyl group, R is carboxy lower alkylcarbamoyl lower alkyl group)), are reported. Among these compounds, however, propanoic acid derivatives have no substituent at 2-position and carbonyl groups exist in all of R group portions, hence the structure differs from that of the inventive compounds, and it is also not described that these compounds have the binding activity to human PPARxcex1 and the transcription-activating function.
As carboxylic acid derivatives with antagonism against fibrinogen receptor, in U.S. Pat. No. 5,227,490 (Merck and Co.,Inc.), compounds represented by a general formula (D) 
(wherein R1 denotes hydrogen atom, C1-6 alkyl group, aryl C4-10 alkyl group, aryl group, carboxyl group, C1-6 alkoxy group, carboxy C0-6 alkyl group, carboxy C0-6 alkoxy group, hydroxy C1-6 alkyl group, C1-4 alkylsulfonyl C0-6 alkyl group, C0-4 alkylamino C0-6 alkyl group, aryl C0-10 alkylamino C0-6 alkyl group, C2-10 acylamino C0-6 alkyl group, C1-4 carboalkoxy C0-6 alkyl group or halogen atom, R2s denote identically or differently hydrogen atoms, halogen atoms, hydroxyl groups, C1-6 alkoxy groups, aryl C0-4 alkyl groups, aryl C0-6 alkoxy groups or C1-6 alkyl groups which may have substituent, R3 denotes hydrogen atom, C1-6 alkyl group or aryl C1-10 alkyl group, X denotes oxygen atom, sulfur atom, SO group, SO2 group, CO group, NR4CO group, CONR4 group, CH2 group, CHxe2x95x90CH group or NR4CS group, Y denotes C1-10 alkyl group which is unsubstituted or which may have substituent, C4-8 cycloalkyl group, aryl group, C0-3 alkyl-aryl C0-3 alkyl group, C0-3 alkylaryl C0-3 alkylcarbonyl group, C0-3 alkylaryl C0-3 alkylcarboxyamide group, C0-3 alkylaryloxy C0-3 alkyl group, CONH group, NHCO group or (CH2)m-Q-(CH2)n (however, Q denotes C3-8 membered heterocycle containing 1 to 3 kinds of heteroatoms selected from oxygen and sulfur, and m and n denote 0 to 4), and Z denotes NR4R5 group (however, R4 and R5 denote identically or differently hydrogen atoms, C1-6 alkyl groups, aryl C1-10 alkyl groups in which alkyl group is unsubstituted or may be substituted with C1-4 alkoxy group, carboxy C0-6 alkyl group, hydroxyl group, halogen atom, or 4-9 membered monocyclic or bicyclic ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) or guanidino group which may have substituent), are reported. However, from the fact that these compounds are amino acid derivatives inevitably containing amino group which may have substituents in all of Z group portions, the structure is different from that of the inventive compounds, and it is also not described that these compounds have the binding activity to human PPARxcex1 and the transcription-activating function.
With respect to patents that report the agonistic effect on PPARxcex1, compounds represented by a general formula (E) 
(wherein Ra denotes 2-benzoxazolyl group or 2-pyridyl group, and Rb denotes methoxymethyl group or trifluoromethyl group), are reported in International Publication Number WO97/25042 (SmithKline Beecham plc.) as compounds with working functions on PPARxcex1 and PPARxcex3. However, the structure of these compounds is different from that of the inventive compounds in that substituents on benzene ring are of disubstituted derivatives at 1-position and 2-position, and further it is not described that they have the binding activity to human PPARxcex1 and the transcription-activating function.
As compounds with agonistic effect on PPARxcex1, in International Publication Number WO97/36579 (Glaxo Welcome Corp.), compounds represented by a general formula (F) 
(wherein X denotes hydrogen atom or fluorine atom), are reported. However, the structure is different from that of the inventive compounds in that these compounds are phenoxyacetic acid derivatives and the position relationship of substituents on benzene ring is of disubstituted form at 1-position and 4-position. Also, the transcription-activating function of PPARxcex1 is never satisfied in strength.
The hyperlipidemia is a risk factor of arteriosclerosis and, from a viewpoint of the prevention of arteriosclerotic diseases, in particular, coronary arteriosclerosis, the development of a therapeutic drug for hyperlipidemia with effectiveness and high safety is desired clinically.
As a result of diligent studies paying an attention to such specific role on the lipidmetabolism of human PPARxcex1, aiming at the creation of structurally novel drug with effectiveness and high safety as a therapeutic drug for hyperlipidemia, the inventors have found that novel substituted phenylpropanoic acid derivatives represented by a following general formula (1) have excellent binding activity to human PPARxcex1 and transcription-activating function and exhibit the lipid-decreasing effect, leading to the completion of the invention. Namely, the invention relates to substituted phenylpropanoic acid derivatives represented by a general formula (1) 
[wherein R1 denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents, R2 denotes a lower alkyl group with carbon atoms of 1 to 4, 2,2,2-trifluoroethyl group, lower alkoxy group with carbon atoms of 1 to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3, phenylthio group or benzylthio group, R3 de-notes a hydrogen atom or lower alkyl group with carbon atoms of 1 to 4 in the case of R2 being lower alkyl group with carbon atoms of 1 to 4 or 2,2,2-trifluoroethyl group, and it denotes a hydrogen atom in the case of R2 being lower alkoxy group with carbon atoms of 1 to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3, phenylthio group or benzylthio group, and R4 denotes a lower alkoxy group with carbon atoms of 1 to 3], their pharmaceutically acceptable salts and their hydrates.
The salts of the compounds represented by the general formula (1) in the invention are of common use and metal salts, for example, alkali metal salts (e.g. sodium salt, potassium salt, lithium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), aluminum salt, and other pharmaceutically acceptable salts are mentioned.
Moreover, the compounds represented by the general formula (1) in the invention sometimes include optical isomers based on the propanoic acid portion. Such isomers and their mixtures are all included in the scope of the invention.
The enantiomers can be prepared through stereoselective synthetic process. Moreover, they can also be prepared by separating diastereomeric ester derivatives or oxazolidinone derivatives obtainable by reacting with optically active alcohol derivatives or optically active oxazolidinone derivatives by a technique of fractional crystallization or chromatography, followed by hydrolysis. Furthermore, they can also be prepared by a technique of chromatography that uses chiral support.
In the general formula (1) of the invention, for xe2x80x9clower alkyl group with carbon atoms of 1 to 4xe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 4 such as methyl, ethyl, propyl, isopropyl and butyl are mentioned.
For xe2x80x9clower alkoxy group with carbon atoms of 1 to 3xe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 3 such as methoxy, ethoxy, isopropoxy and propoxy are mentioned.
For xe2x80x9chalogen atomsxe2x80x9d, fluorine atom, chlorine atom, bromine atom and iodine atom are mentioned.
For xe2x80x9clower alkylthio group with carbon atoms of 1 to 3xe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 3 such as methylthio, ethylthio and propylthio are mentioned.
For substituents acceptable in xe2x80x9cphenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituentsxe2x80x9d, lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, halogen atom or trifluoromethyl group are mentioned.
The compounds of the invention can be prepared, for example, through following processes (Scheme 1). 
Namely, compounds represented by a general formula (1b) 
[wherein R1 denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents, R2xe2x80x2 denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3 or phenoxy group, and R4 denotes a lower alkoxy group with carbon atoms of 1 to 3], can be prepared by reacting (Wittig reaction or Horner-Emmons reaction; first process) compounds represented by a general formula (2) 
[wherein R4 is as described above], and by a general formula (6) 
[wherein R2xe2x80x2 is as described above, R5 is a lower alkyl group with carbon atoms of 1 to 4, and X denotes PPh3 group or PO(OC2H5)2 group], in the presence of base, to synthesize compounds represented by a general formula (3) 
[wherein R2xe2x80x2, R4 and R5 are as described above], by reducing and hydrogenolysis (second process) of these compounds, to obtain compounds represented by a general formula (4) 
[wherein R2xe2x80x2, R4 and R5 are as described above], by reacting (third process) these compounds with compounds represented by a general formula (7) 
[wherein R1 is as described above], to obtain compounds represented by a general formula (5) 
[wherein R1, R2xe2x80x2, R4 and R5 are as described above], and by hydrolizing (fourth process) COOR5 position of these compounds.
In the Wittig reaction or Horner-Emmons reaction of the first process, as the base, for example, alkali metal hydride such as sodium hydride, organometallic compound such as butyl lithium, metal amide such as lithium diisopropylamide, or metal alkoxides such as sodium methoxide or potassium t-butoxide can be used in a solvent such as tetrahydrofuran, toluene, dioxane or N,N-dimethylformamide. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C.
The reduction being the second process can be performed at a hydrogen pressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate or N,N-dimethyl-formamide in the presence of metallic catalyst such as palladium on activated carbon, platinum on activated carbon, platinum oxide or rhodium on alumina. The reaction can be performed at a reaction temperature of 0xc2x0 C. to 100xc2x0 C., preferably room temperature to 80xc2x0 C.
The condensation of the third process can be performed by leaving carboxyl group as it is or converting it to reactive derivatives.
As the xe2x80x9creactive derivative groups of carboxyl groupxe2x80x9d, acid chloride, acid bromide, acid anhydride, carbonylimidazole or the like is mentioned. In the case of the reaction using reactive derivatives, the reaction can be performed in a solvent such as dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydride such as sodium hydride, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base.
In the case of the condensation by using leaving carboxylic acid form as it is, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in the presence or absence of base, and further in the presence or absence of additive.
As the condensing agent, for example, dicyclohexylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoric azide, carbonyldiimidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C.
The hydrolysis of the fourth process can be performed under alkaline condition. For the alkaline condition, lithium hydroxide, sodium hydroxide, potassium hydroxide or the like is used. The reaction can be performed at a reaction temperature of 0xc2x0 C. to 80xc2x0 C., preferably room temperature to 60xc2x0 C.
Moreover, compounds represented by the general formula (1b) can also be synthesized through following processes (Scheme 2). 
Namely, compounds represented by the general formula (1b) [wherein R1, R2xe2x80x2 and R4 are as described above], can be prepared by reacting (Wittig reaction or Horner-Emmons reaction; fifth process) compounds represented by a general formula (8) 
[wherein R1 and R4 are as described above], with compounds represented by the general formula (6) 
[wherein R2xe2x80x2, R5 and X are as described above], in the presence of base, to synthesize compounds represented by a general formula (9) 
[wherein R1, R2xe2x80x2, R4 and R5 are as described above], by reducing (sixth process) these compounds, to obtain compounds represented by the general formula (5) 
[wherein R1, R2xe2x80x2, R4 and R5 are as described above], and by hydrolyzing (seventh process) COOR5 position of these compounds.
The reaction of the fifth process can be performed through the process similar to the reaction of the first process. The reaction of the sixth process can be performed through the process similar to the reaction of the second process. The reaction of the seventh process can be performed through the process similar to the reaction of the fourth process.
Compounds represented by a general formula (1c) can be synthesized through following processes (Scheme 3). 
Namely, compounds represented by the general formula (1c) 
[wherein R1 denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents, R2xe2x80x3 denotes a lower alkylthio group with carbon atoms of 1 to 3, phenylthio group or benzylthio group, and R4 denotes a lower alkoxy group with carbon atoms of 1 to 3], can be prepared by reducing (reduction reaction) nitro group of compounds represented by a general formula (10) 
[wherein R1 and R4 are as described above], and then conducting Meerwein arylation reaction (eighth process), to obtain compounds represented by a general formula (11) 
[wherein R1 and R4 are as described above, R5 is a lower alkyl group with carbon atoms of 1 to 4, and Y denotes a halogen atom], by reacting (ninth process) these compounds with compounds represented by a general formula (13) 
[wherein R2xe2x80x3 is as described above], in the presence of base, to obtain compounds represented by a general formula (12) 
[wherein R1, R2xe2x80x3, R4 and R5 are as described above], and by hydrolyzing (tenth process) COOR5 portion [R5 is as described above] of these compounds.
The reaction of the eighth process can be performed first at a hydrogen pressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide in the presence of metallic catalyst such as palladium on activated carbon, platinum on activated carbon, platinum oxide or rhodium on alumina. The reaction can be performed at a reaction temperature of 0xc2x0 C. to 100xc2x0 C., preferably room temperature to 80xc2x0 C. Next Meerwein arylation reaction can be performed by reacting sodium nitrite in aqueous solution of hydrogen halide such as hydrochloric acid or hydrobromic acid to synthesize diazonium salt, and then by adding acrylic ester such as methyl acrylate or ethyl acrylate and cuprous salt such as copper oxide (I). The synthesis of diazonium salt can be performed at a reaction temperature of xe2x88x9240xc2x0 C. to 0xc2x0 C., preferably xe2x88x9220xc2x0 C. to xe2x88x925xc2x0 C. Next reaction with acrylic ester can be performed at 0xc2x0 C. to 50xc2x0 C., preferably room temperature to 40xc2x0 C.
The reaction of the ninth process can be performed in a solvent such as ethanol, methanol or N,N-dimethylformamide, using, for example, alkali metal hydride such as sodium hydride, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or the like as a base. The reaction can be performed at a reaction temperature of room temperature to 180xc2x0 C., preferably at reflux temperature of the solvent.
The reaction of the tenth process can be performed through the process similar to the reaction of the fourth process.
Compounds represented by a general formula (1d) can be synthesized through following processes (Scheme 4). 
Namely, compounds represented by the general formula (1d) 
[wherein R1 denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents, R2xe2x80x2xe2x80x3 denotes a lower alkyl group with carbon atoms of 1 to 4 or 2,2,2-trifluoroethyl group, R3 denotes a hydrogen atom or lower alkyl group with carbon atoms of 1 to 4, and R4 denotes a lower alkoxy group with carbon atoms of 1 to 3], can be prepared by reacting (Tetrahedron Letters, 1997, 38, 2645; eleventh process) compounds represented by a general formula (14) 
[wherein R4 is as described above], with compounds represented by a general formula (22) 
[wherein R2xe2x80x2xe2x80x3 and R3 are as described above, R5 is a lower alkyl group with carbon atoms of 1 to 4, and Z denotes a trimethylsilyl group or t-butyldimethylsilyl group], in the presence of a catalytic amount of Lewis acid, to synthesize compounds represented by a general formula (15) 
[wherein R2xe2x80x2xe2x80x3, R3, R4 and R5 are as described above], by hydrogenolysis (twelfth process) these compounds, to obtain compounds represented by a general formula (16) 
[wherein R2xe2x80x2xe2x80x3, R3, R4 and R5 are as described above], by reacting (thirteenth process) these compounds with compounds represented by the general formula (7) 
[wherein R1 is as described above], to obtain compounds represented by a general formula (17) 
[wherein R2xe2x80x2xe2x80x3, R3, R4 and R5 are as described above], and by hydrolyzing (fourteenth process) COOR5 position of these compounds.
The reaction of the eleventh process can be performed in a solvent such as dichloromethane, tetrahydrofuran, toluene or dioxane, using, for example, magnesium perchlorate, magnesium bistrifluoromethanesulfonylimide, titanium tetrachloride or the like as a Lewis acid. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 80xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C.
The reaction of the twelfth process can be performed through the process similar to the reaction of the second process. The reaction of the thirteenth process can be performed through the process similar to the reaction of the third process. The reaction of the fourteenth process can be performed through the process similar to the reaction of the fourth process.
Moreover, optically active compounds of the general formula (1a) can be prepared, for example, through following processes (Scheme 5). 
Namely, optically active substituted phenylpropanoic acid derivatives represented by the general formula (1a) 
[wherein R1 denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents, R2 denotes a lower alkyl group with carbon atoms of 1 to 4, 2,2,2-trifluoroethyl group, lower alkoxy group with carbon atoms of 1 to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3, phenylthio group or benzylthio group, and R4 denotes a lower alkoxy group with carbon atoms of 1 to 3], can be prepared by reacting (fifteenth process) compounds represented by the general formula (2) 
[wherein R4 is as described above], with compounds represented by a general formula (18) 
[wherein R2 is as described above, and Xp denotes a chiral oxazolidinone derivative with absolute configuration being (S) such as (S)-4-benzyl-2-oxazolidinone-3-yl group, (S)-4-isopropyl-2-oxazolidi-none-3-yl group or (S)-4-phenyl-2-oxazolidinone-3-yl group, or the like], in the presence of metal ligand and base, to synthesize compounds represented by a general formula (19) 
[wherein R2, R4 and Xp are as described above], by eliminating hydroxyl group of these compounds and hydrogenolysis (sixteenth process), to obtain compounds represented by a general formula (20) 
[wherein R2, R4 and Xp are as described above], by reacting (seventeenth process) these compounds with compounds represented by the general formula (7) 
[wherein R1 is as described above], to obtain compounds represented by a general formula (21) 
[wherein R1, R2, R4 and Xp are as described above], and by hydrolyzing (eighteenth process) COXp position of these compounds.
The reaction of the fifteenth process can be performed in a solvent such as tetrahydrofuran, methylene chloride or diethyl ether, using di-n-butylboryltrifurate, diethylboryltrifurate, titanium tetrachloride or the like as a metal ligand and tertiary amine such as triethylamine, diisopropylethylamine or ethyldimethylamine as a base. The reaction can be performed at a reaction temperature of xe2x88x92100xc2x0 C. to room temperature, preferably xe2x88x9280xc2x0 C. to 0xc2x0 C.
The reaction of the sixteenth process can be performed in a solvent such as acetic acid or trifluoroacetic acid in the presence of triethylsilane or trichlorosilane. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 50xc2x0 C., preferably 0xc2x0 C. to room temperature.
The reaction of the seventeenth process can be performed through the process similar to the reaction of the third process.
The reaction of the eighteenth process can be performed under alkaline condition. For alkaline condition, lithium hydroxide, sodium hydroxide, mixture of lithium hydroxide with hydrogen peroxide, or the like is used. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C.
Moreover, optically active compounds being said general formula (1a) can be prepared, for example, through following processes (Scheme 6). 
Namely, optically active substituted phenylpropanoic acid derivatives represented by the general formula (1a) 
[wherein R1 denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents, R2 denotes a lower alkyl group with carbon atoms of 1 to 4, 2,2,2-trifluoroethyl group, lower alkoxy group with carbon atoms of 1 to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3, phenylthio group or benzylthio group, and R4 denotes a lower alkoxy group with carbon atoms of 1 to 3], can be prepared by reacting compounds represented by the general formula (1e) 
[wherein R1, R2 and R4 are as described above], with pivaloyl chloride in the presence of base, to obtain compounds represented by a general formula (23) 
[wherein R1, R2 and R4 are as described above], by reacting (nineteenth process) these compounds with compounds represented by a general formula (24) 
[wherein Xpxe2x80x2 denotes an optically active chiral oxazolidinone derivative such as optically active 4-benzyl-2-oxazolidinone-3-yl group, 4-isopropyl-2-oxazolidinone-3-yl group or 4-phenyl-2-oxazolidinone-3-yl group, amide derivative, sultam derivative or the like], in the presence of base, to synthesize compounds represented by a general formula (25) 
[wherein R1, R2, R4 and Xpxe2x80x2 are as described above], by separating each diastereomer of these compounds by fractional recrystallization or column chromatography, to obtain compounds represented by a general formula (26) 
[wherein R1, R2, R4 and Xpxe2x80x2 are as described above], and by hydrolyzing (twentieth process) Xpxe2x80x2 portion of these compounds.
In the reaction of the nineteenth process, first, the synthesis of compounds represented by the general formula (23) 
[wherein R1, R2 and R4 are as described above], can be performes in a solvent such as tetrahydrofuran, methylene chloride or diethyl ether, using tertiary amine such as triethylamine, diisopropylethylamine, ethyldimethylamine or pyridine as a base. The reaction can be performed at a reaction temperature of xe2x88x92100xc2x0 C. to room temperature, preferably xe2x88x9240xc2x0 C. to 0xc2x0 C.
Next, the reaction between general formula (23) 
[wherein R1, R2 and R4 are as described above], and the general formula (24) 
[wherein Xpxe2x80x2 is as described above], can be performed in a solvent such as tetrahydrofuran, methylene chloride or diethyl ether, in the presence of a base of alkali metal hydride such as sodium hydride, organometallic compound such as butyl lithium, metal amide such as lithium diisopropylamide, or metal alkoxide such as sodium methoxide or potassium t-butoxide, or the like. The reaction can be performed at a reaction temperature of xe2x88x92100xc2x0 C. to room temperature, preferably xe2x88x9240xc2x0 C. to 0xc2x0 C.
The reaction of the twentieth process can be performed under alkaline condition. For alkaline condition, lithium hydroxide, sodium hydroxide, mixture of lithium hydroxide with hydrogen peroxide, or the like is used. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C.
Moreover, optically active compounds being said general formula (1a) can also be prepared, for example, through following processes (Scheme 7). 
Namely, optically active substituted phenylpropanoic acid derivatives represented by the general formula (1a) 
[wherein R1 denotes a lower alkyl group with carbon atoms of 1 to 4, lower alkoxy group with carbon atoms of 1 to 3, trifluoromethyl group, trifluoromethoxy group, phenyl group which is unsubstituted or may have substituents, phenoxy group which is unsubstituted or may have substituents or benzyloxy group which is unsubstituted or may have substituents, R2 denotes a lower alkyl group with carbon atoms of 1 to 4, 2,2,2-trifluoroethyl group, lower alkoxy group with carbon atoms of 1 to 3, phenoxy group, lower alkylthio group with carbon atoms of 1 to 3, phenylthio group or benzylthio group, and R4 denotes a lower alkoxy group with carbon atoms of 1 to 3], can be prepared by reacting (twenty-first process) compounds represented by a general formula (27) 
[wherein R4 is as described above], with compounds represented by a general formula (30) 
[wherein R2 is as described above, and Xpxe2x80x3 denotes a chiral oxazolidinone with absolute configuration being (R) such as (R)-4-benzyl-2-oxazolidinone-3-yl group, (R)-4-isopropyl-2-oxazolidinone-3-yl-group or (R)-4-phenyl-2-oxazolidinone-3-yl group, chiral imidazolidinone, chiral cyclic lactam, chiral sultam or the like], in the presence of base, to afford compounds represented by a general formula (28) 
[wherein R2, R4 and Xpxe2x80x3 are as described above], which was hydrogenolysed (twenty-second process) in the presence of base to obtain compounds represented by a general formula (29) 
[wherein R2, R4 and Xpxe2x80x3 are as described above], by reacting (twenty-third process) these compounds with compounds represented by the general formula (7) 
[wherein R1 is as described above], to obtain compounds represented by a general formula (26a) 
[wherein R1, R2, R4 and Xpxe2x80x3 are as described above], and by hydrolyzing (twenty-fourth process) COXpxe2x80x3 position of these compounds.
For the reaction of the twenty-first process, for example, alkali metal hydride such as sodium hydride, organometallic compound such as butyl lithium, metal amide such as lithium diisopropylamide or sodium bis(trimethylsilyl)amide can be used as a base in a solvent such as tetrahydrofuran, diethyl ether or hexane. The reaction can be performed at a reaction temperature of xe2x88x92100xc2x0 C. to room temperature, preferably xe2x88x9280xc2x0 C. to 0xc2x0 C.
The reaction of the twenty-second process can be performed at a hydrogen pressure of 98.1 kPa to 491 kPa in a solvent such as ethanol, methanol, tetrahydrofuran, ethyl acetate or N,N-dimethylformamide in the presence of metallic catalyst such as palladium on activated carbon, platinum on activated carbon, platinumoxide or rhodium on alumina. The reaction can be performed at a reaction temperature of 0xc2x0 C. to 100xc2x0 C., preferably room temperature to 80xc2x0 C.
The reaction of the twenty-third process can be performed by leaving carboxyl group as it is or converting it to reactive derivatives. As the xe2x80x9creactive derivative group of carboxyl groupxe2x80x9d, acid chloride, acid bromide, acid anhydride, carbonylimidazole or the like is mentioned.
In the case of the reaction using reactive derivative, the reaction can be performed in a solvent such as dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydride such as sodium hydride, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base.
In the case of conducting the reaction by leaving carboxylic acid form as it is, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in the presence or absence of base, and further in the presence or absence of additive.
As the condensing agent, for example, dicyclohexylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoric azide, carbonyldiimidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C.
The reaction of the twenty-fourth process can be performed under alkaline condition. For alkaline condition, lithium hydroxide, sodium hydroxide, mixture of lithium hydroxide with hydrogen peroxide, or the like is used. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 50xc2x0 C.
As the administrating form of the inventive novel compounds, for example, oral administration with tablet, capsule, granule, powder, inhalant, syrup or the like, or parenteral administration with injection, suppository or the like can be mentioned.
Best embodiment to put the invention into practice